Tu1250

Clinical Response to Medical Treatment and Prognosis of Cronkhite-CanadaSyndrome - A Japanese Nationwide SurveyChikako Watanabe, Kazuyuki Narimatsu, Hirokazu Sato, Shingo Usui, Shunsuke Komoto,Kengo Tomita, Ryota Hokari, Soichiro Miura

Background: Cronkhite-Canada Syndrome (CCS) is an uncommon gastrointestinal polyposissyndrome that exists mostly in Japan characterized by dermatologic manifestations associatedwith chronic diarrhea, malnutrition, and protein wasting that can be fatal in as high as 50%if untreated or if treatment is delayed or inadequate. Due to its rarity, its subjects cannotbe studied in clinical trials. Here, we report patient characteristics derived from a nationaldatabase in an effort to identify prognostic factors and to improve treatment outcomes.Method: Retrospective analysis of 150 patients with CCS from a national database including80 institutions specializing in gastroenterology. Clinical features including endoscopic find-ings, treatment, prognosis, and response to medical therapy were included. This study wassupported by Intractable Disease, Health and Labor Sciences research groups for the JapaneseMinistry of Health, Labor and Welfare. Results: Patient's age was 68.1±9.7 and treatmentduration was 6.0±4.6years. CCS-related polyposis endoscopically confirmed to be throughoutthe gastrointestinal tract. Of the 140 patients who received steroids, 5 failed to respond, 2underwent colectomy due to massive bleeding, 2 received cyclosporine, and 1 receivedbiologics. Improvement of diarrhea followed by recovery of hypoalbuminemia was observedusually within 3 months after the start of medical therapy, with weight gain and improvementof dermatologic manifestations occurring at 5-6.5 months, and improvement of endoscopicappearance by 7.7 months. In 17%, no improvement of polyposis occurred despite clinicalresponse. CCS-related gastric and colonic polyps progressed to advanced gastric and coloncancer in 7 of 107 and 15 of 120, respectively, suggesting the importance of endoscopicfollow-up. Among those who discontinued steroid therapy, 7.4% developed advanced cancer,compared with 2.7% in those who maintained clinical remission with steroids. No patientwho received nutritional support alone experienced clinical remission. An induction doseof steroid of >0.5mg/kg, followed, in some cases, with steroid maintenance appeared beneficialfor preventing the risk of recurrence of CCS-related polyps, reducing cancer risk, underscor-ing the importance of maintaining endoscopic remission. As for prognosis, 108 patientswere alive and 22 had expired. The causes of death were colon cancer (1), gastric cancer(2), other malignancies (5), and other diseases, but none died of malnutrition. Conclusion:Contrary to earlier reports, the prognosis of CCS has greatly improved through improvedmedical treatment, although the course of CCS is relentlessly progressive with high cancerrisk. A sufficiently high induction steroid dose, long-term steroid maintenance, and aggressivenutritional support appear to improve the natural history of CCS.

Tu1251

Mitochondrial Neurogastrointestinal Encephalomyopathy: The Liver As aTissue Source to Restore Thymidine Phosphorylase ActivityElisa Boschetti, Rocco Latorre, Vitaliano Tugnoli, Valerio Carelli, Francesca Bianco, ElenaBonora, Giovanni Barbara, Vincenzo Stanghellini, Roberto De Giorgio

Objectives Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare auto-somal recessive disease associated with the nuclear TYMP gene mutations. As a result, thethymidine phosphorylase (TP) activity is markedly reduced / lacking leading to mitochondrialDNA point mutations, multiple deletions and depletion. MNGIE is characterized by severegastrointestinal (GI) dysmotility (i.e. gastroparesis and intestinal pseudo-obstruction) andneurological impairment. Typical MNGIE patients have ~5% of TP residual activity withsymptom onset in the second decade and a life expectancy limited to the forth decade. Incontrast, MNGIE relatives (heterozygous for TYMP mutations) show ~25-35% of TP residualactivity and never manifest the syndrome. Such threshold may represent the target for newtreatments. So far, there are no established therapeutic options for MNGIE. In order torestore a normal TP activity, allogenic hematopoietic stem cell transplantation (AHSCT) hasbeen used as a cellular source of TP. Data on ~20 MNGIE patients undergone AHSCTshowed GI and neurological improvement, although the 5-year survival rate is ~26%. Thus,other organ transplantation may represent an alternative for MNGIE patients. Since the liveris the main organ for protein biosynthesis and the transplantation success is estimated at~90% of cases, the aim of this study was to test whether this organ can be a reliable sourceof TP. Methods A number of n= 11 patients (7 males; age range: 35-55 years) undergonehepatic resection for focal disorders (i.e., uncomplicated tumors in non-cirrhotic liver) wereexamined. Margins of normal liver tissue were processed for a variety of methodologicalapproaches aimed to identify, quantify and localize TP protein, i.e. western blotting (WB),ELISA, and immunohistochemistry. TYMP mRNA specific expression has been evaluatedvia qPCR. We used bone marrow and intestinal mucosa as positive, while skeletal muscleand MNGIE buffy coat as negative controls. Results WB showed TP protein in liver tissuewith a densitometric ratio TP/GAPDH of 0.9 ± 0.5 A.U. ELISA determined a TP content of0.5 ± 0.07 ng/ug total proteins. Notably, the liver TP concentration was six time more thanthat of bone marrow (P <0.05), while negative controls did not have any detectable signal.TP immunoreactivity was localized in nuclei and cytoplasm of hepatocytes as well as inreticular cells. TYMP mRNA detection provided evidence of in situ liver synthesis. Bonemarrow, liver, and duodenum expressed TYMP at a comparable level, whereas no expressionwas identified in the skeletal muscle. Conclusions The results of this study demonstrate thatthe liver can be a reliable source of TP, providing a rationale for liver transplantation inMNGIE patients.

S-795 AGA Abstracts

Tu1253

Regenerating Islet-Derived 3-Alpha As Biomarker for Small Intestinal Damageand Its Significance in the Management of Celiac Disease PatientsIrene Marafini, Francesca Zorzi, Silvia Sedda, Ivan Monteleone, Maria Laura Cupi, GinoRoberto Corazza, Francesco Pallone, Antonio Di Sabatino, Giovanni Monteleone

Background and aim: Measuring intestinal damage caused by infectious and immune-mediated pathologies is objectively difficult and clinicians often rely on invasive tests todiagnose small intestinal epithelial loss. Regenerating islet-derived 3-α (REG3α), an antimi-crobial protein expressed in Paneth cells, has been recently proposed as a predictor ofgraft-versus host disease. We aimed to ascertain whether serum REG3α concentration is aquantitative parameter of small intestinal damage. Materials and methods: REG3α wasevaluated in serum samples of 37 patients with active celiac disease (ACD), 11 patients withrefractory celiac disease (RCD), 6 patients with common variant immune-deficiency (CVID),and 11 patients with ileal Crohn's disease. Additionally, serum samples were taken from 9CD patients before and after a long-term and successful gluten-free-diet (GFD). Normalcontrols included 8 patients with irritable bowel syndrome (IBS). In all the patients, intestinaldamage was investigated by upper and/or lower intestinal endoscopy and histological analysisof biopsy samples. Sera were also available from 18 normal volunteers. Results: Optimalcut-off value of the assay, determined using serum samples of normal volunteers, was 191ng/ml. Increased values of REG3alpha were found in 33/37 (89%) of ACD patients, 11/11(100%) of RCD patients, 6/6 (100%) CVID patients, 11/11 (100%) Crohn's disease patientsand 0/8 IBS patients. Serum REG3alpha levels in ACD (median: 560, range: 137-1120 ng/ml), RCD (median: 610, range: 214-1567 ng/ml), CVID (median: 1196, range: 504-1635ng/ml) and Crohn's disease (median 332; range: 226-647 ng/ml) were significantly higherthan that in control group (median: 79; range: 0-167 ng/ml) (P<0.0002). Sensitivity andspecificity of the assay for the overall group of patients with intestinal damage were respec-tively 93% and 100% (PPV 100%, NPV 87%). A significant decrease of REG3alpha wasseen in all CD patients following 6-12 months of GFD (median 737 ng/ml; range: 340-1115 ng/ml at baseline vs median 277; range 90-477 ng/ml after a GFD; P<0.004). Conclu-sions: REG3α is a useful biomarker of intestinal damage, which can be combined withclinical data to identify patients who should undergo invasive tests for diagnosing tissue-damaging enteropathies.

Tu1254

Glitazones in the Treatment of Angioectasias: Regulating the TGF-β SignalingPathway, PPARγ, Angiogenesis and Wound Repair MechanismsMayur Sarangdhar, Mary Beth Yacyshyn, Bruce J. Aronow, Bruce Yacyshyn

Introduction: Angioectasias (AEs) are poorly understood vascular abnormalities in the GItract and the most common source of bleeding but their treatment options are limited.Bleeding and pathology similar to AEs are linked with decreased VEGF signaling and useof anti-angiogenic therapies, however increased expression of VEGF has been observed inAEs suggesting defects in downstream signaling pathways. We theorize that defects inangiogenesis signaling lead to oxidative stress, increase in severity of some cause of AEs butmay be overcome by therapies limiting the magnitude of hypoxia-associated oxidative stress.To mitigate these pathological mechanisms, we hypothesized that by virtue of targetingwound-response amplifying pathways, glitazones or sartans have the potential to decreasewound-associated signaling and present novel therapeutic applications for the treatment ofAEs. Methods: To test for the potential of approved drugs to impact AE-associated diseasepathology, we used data from the FDA's Adverse Event Reporting System (AERS) as normal-ized within AERSMine, a phenome-pharmacome web datamine that we developed. Wecompared differential rates of GI-related complications in four mutually exclusive treatmentcohorts based on individuals who were on any glitazone (G, n=46676), sartan (S, n=74664),S+G (n=125,112), or non-S, non-G drugs (Rx, n=2,848,590) in male/female and adults/elderly strata. Cancer-associated indication subgroups were excluded from all cohorts. Tominimize confounder GI-related complications, all reports with NSAIDs use were alsoexcluded. Results: Individuals who used glitazones significantly under-reported the occur-rence of GI hemorrhage (rr=0.4), occult blood (0.75), hematochezia (0.25) and melena(0.38). Through high dimensional biological network modeling from 18 different mouseknockout models associated with GI bleeding, VEGF signaling defects and loss of vWF, weidentified a set of linked pathways associated with increased oxidative stress and increasedsignaling of VEGF, FGF2 and TGF-β. These significant pathways potentially exaggerateinjury responses, fluid dysregulation and impair wound healing through abnormal bloodcoagulation, altered fibrin clot formation and angiogenesis. Hypoxic downregulation ofPPARγ inhibits the expression of NRF2 while upregulating NF-κB thereby inducing inflamma-tion. We show that glitazones and sartans significantly reduce risk of GI complications viaincreased expression of PPARγ and inhibitory Smad proteins to modulate TGFβ signaling.Conclusions: Glitazones and sartans demonstrate a promising therapeutic role in minimizingthe risk of AEs and resultant bleeding by regulating angiogenesis and wound healing throughcomplex HIF1α-VEGF-TGFβ and PPARγ-NRF2 mechanisms. We are currently accruingpatient samples to validate these biomarkers and discover new insights for treatment of AEs.

Tu1255

Detection of Urinary Volatile Organic Compounds in Patients WithInflammatory Bowel Disease and Controls by an Electronic Nose - ATransatlantic StudyJames Covington, Ruth Harbord, Eric W. Westenbrink, Catherine Bailey, Nicola O'connell,Amritpal Dhaliwal, Chuka Nwokolo, Anne Foley, Neil B. Marya, Veronica Baptista, KarnaDev Bardhan, David R. Cave, Ramesh Arasaradnam

Background: Resident colonic bacteria (anaerobes and firmicutes) ferment undigested fibre.The balance between their large species number is influenced by the host genetic make up.An individuals ‘fermentation profile' (FP) is therefore likely to comprise a stable ‘personalsignature' and can be perturbed in disease states e.g. inflammatory bowel disease (IBD). Amethod of monitoring the FP is by analysing the volatile organic compounds (VOC) that

AG

AA

bst

ract

s